This project will examine the effects of lymphatic vessel growth and remodeling on the severity of lung inflammation. Effects of changes in lymphatics on lung function and inflammatory responses are poorly understood and offer new therapeutic strategies. The project will determine the mechanisms of development and consequences of lymphatic vessel abnormalities in lung inflammation, assess changes in severity and susceptibility to subsequent inflammatory insults, and explore novel strategies for preventing, eliminating, or normalizing the abnormalities. Specific Aim #1 builds on evidence that lymphatics grow and undergo remodeling in sustained inflammation, and impaired fluid and cell flux through abnormal lymphatics can exaggerate edema and alter inflammatory responses. Yet, expansion of a more normal lymphatic network can reduce inflammatory responses by improving tissue fluid drainage and immune cell traffic. New mouse models and complementary technologies will be exploited to address these issues. We will first test the hypothesis that lymphatic growth or remodeling can influence inflammatory responses in the lung. The approach will be to compare the mechanisms and consequences of remodeling of lung lymphatics in three mouse models recently found to have robust but very different changes in lymphatics. A new transgenic mouse model, where non- inflammatory growth of lymphatics in otherwise normal airways and lung is driven by overexpression of VEGF- C, will be compared to models where lymphatic growth accompanies lung inflammation. The goals are to identify factors that drive lymphatic remodeling and distinguish abnormalities in lymphatics that exaggerate inflammation from changes that reduce inflammation. Specific Aim #2 builds on evidence that, unlike new blood vessels, new lymphatics usually do not regress when inflammation resolves and influence subsequence inflammatory responses. Pathways that promote lymphatic endothelial cell survival have been identified in recent years. These are potential targets for eliminating abnormal lymphatics. Here, we will test the hypothesis that abnormal lymphatics that persist after lung inflammation resolves can be eliminated or normalized by blocking pathways that promote endothelial cell survival. Strategies that prevent lymphatic growth (prevention models) will be compared to approaches that eliminate lymphatics (reversal models) or normalize lymphatics (normalization models). The effectiveness of blocking VEGFR-2 and VEGFR-3 signaling will be compared to effects of blocking mTOR or other pathways that support endothelial cell survival. Together, the results will provide mechanistic insights into the contribution of abnormalities in lung lymphatics to the severity of asthma, bronchitis, pneumonia, and other lung disease accompanied by sustained inflammation.